From Gene to Pathway to Drug: Exploring the Biosynthesis of Hyperforin and Polycyclic Polyprenylated Acylphloroglucinol (PPAPs) in family Hypericaceae.

S. Wu, E. C. Tatsis

CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 300 Feng Lin Rd, Xuhui District, Shanghai 200032, China

Hypericum perforatum, commonly known as St John's wort (SJW), is one of the most important medicinal plants, with annual global sales over US$ 6 billion. The meroterpenoid hyperforin is considered to be responsible for the antidepressant properties of SJW extracts, but the genes controlling its biosynthesis are unknown. Using genome mining and biochemical work, we characterize two biosynthetic gene clusters (BGCs) that encode the first three steps in the biosynthesis of hyperforin. The syntenic and phylogenetic analyses reveal the parallel assembly of the two BGCs. The syntenous BGC in Mesua ferrea indicates that the first cluster was assembled before the divergence of the Hypericaceae and Calophyllaceae families. The assembly of the second cluster is the result of a coalescence of genomic fragments after a major duplication event. The parallel assembly of two BGCs with similar compositions in a single plant species is uncommon, and our work provides insights into how and when these gene clusters form. Our discovery helps to advance our understanding of the evolution of plant specialized metabolism and its genomic organization. Additionally, our results offer a foundation from which hyperforin biosynthesis can be more fully understood, and which can be used in future metabolic engineering applications.